At the Korea Research Institute of Standards and Science, a microprobe mode (spatial resolution: micron level and low-throughput) laser based matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) imaging equipment (previously filed and registered as a patent) rather than a microscope mode was manufactured and used together with a microprobe mode (spatial resolution: a 100 nm and low-throughput) time-of-flight secondary ion mass spectroscopy (TOF-SIMS) imaging equipment coupled with a cluster ion beam, such that research into a possibility for achieving early stage diagnosis of diseases and realization of personalized medicine diagnosis through mass imaging of a biological tissue has been conducted in collaboration with Seoul National University Hospital, National Cancer Center, Dong-A University Hospital, Yonsei University Health System, Samsung Hospital, and the like. In addition, research into development of new medicine and diagnosis has been conducted by searching and discovering metabolome (GC-MS), genes, and proteins (MALDI-TOF) related markers using various mass analyzing conventional equipment from foreign companies in a number of national research and development (R&D) business including a proteomics utilizing technology development business (21C frontier research development business). As described above, at the Korea Research Institute of Standards and Science, the microprobe mode MALDI imaging equipment having a micron level of spatial resolution (hereinafter, referred to as Prior Art 1) was manufactured and applied to an mass imaging of various bio samples; however, the equipment has a low-throughput having a limitation in a measuring speed as described in the above description, which may be possibly be utilized at a R&D research facility rather than in a hospital or a health examination center.
Further, German Cancer Research Center and Arlinghaus professor group of Munster University use an ion beam based TOF-SIMS imaging technology for PNA-DNA microarray imaging and research into a technology of removing cancer cell by a boron neutron capture therapy (BNCT). In addition, at the Korea Research Institute of Standards and Science, a cluster ion beam based TOF-SIMS imaging technology was used to research human skin, retina, heart, cardiovascular, colon tissues and body samples (serum, stool, and the like) provided from Seoul National University Hospital (ophthalmology, dermatology), Yonsei University Health System, Samsung Hospital, and National Cancer Center, such that disease research at metabolome and lipids level, diagnosis, a difference between individual chemotherapy and chemoradiation have been researched (hereinafter, referred to as Prior Art 2). However, the above-mentioned technologies still have a low-throughput due to limitation in the measuring speed since an imaging measurement is performed in a microprobe mode).
US Sequenom Inc. performed a large scaled single nucleotide polymorphism (SNP) research in collaboration with National Cancer Institute (NCI) in 2001 and published a paper ““High Throughput Development and Characterization of a Genome-Wide Collection of Gene-Based SNP Markers by chip-based MALDI-TOF” (hereinafter, referred to as Prior Art 3) in Proceedings of the National Academy of Sciences (PNAS). In Prior Art 3, an automatic analysis method and a MassARRAY system by Sequenom were used and analysis was performed 9,000 or more times on 94 people to successively find 3,148 SNPs, which were not known until now. Through this research, it may be considered that automation of SNP analysis is capable of being achieved and SNP for a number of people is capable of being analyzed in one reaction by treating a DNA sample together.
In addition, Heeren professor group of Netherlands FOM institute developed a novel microscope mode MALDI imaging equipment and secured a micron level of spatial resolution imaging technology (hereinafter, referred to as Prior Art 4). Further, in accordance with global trend of drug discovery, disease diagnosis, and biomarker discovery research by the mass imaging of the biotissue, imaging MALDI mass spectrometers have been released by world's leading mass spectrometer companies such as US Applied Biosystems, Waters and German Bruker-Daltonics since 2000.
However, the above-described equipments according to the Prior Arts or the MALDI imaging research currently conducted by world's leading research groups (including US Caprioli, and the like) and national research groups (including Konkuk University) has actual spatial resolution of merely about 30 to 50 μm or does not still overcome the limitation in the measuring speed. Information capable of being obtained by the spatial resolution is merely for direct profiling from the tissue rather than an imaging grade, and therefore, in order to achieve a minimal and meaningful imaging, securing the micro level of the spatial resolution is urgently required.
FIG. 1 shows differences between a microprobe mode and a microscope mode. In order to obtain a mass chemistry imaging or a mass spectrum in both of a laser based MALDI-TOF or an ion beam based TOF-SIMS as which are commercially available in the spectrometer market as conventional equipment from both of the inside and outside of the country, data may be obtained by scanning a sample surface in the microprobe mode with pixel-by-pixel (for example, 256×256) (see FIG. 1). Therefore, since the measuring speed (1 sample/sec for MALDI-TOF, 0.01 sample/sec for TOF-SIMS) is too low to be used in hospital or a medical diagnostic system for health examination, the above-described equipment are merely used in R&D research but the utilization range thereof has a limitation. In the above-described Prior Art 4, a micro level of spatial resolution imaging technology was secured and various technologies were introduced in order to increase the measuring speed; however, as shown in FIG. 1, since position sensitive detector (x, y) & mass gating (Δt) was used, mass range should be selected, such that a problem that mass analysis of an unknown sample is not capable of being performed still needs to be solved.
In addition, according to the above-described Prior Arts, molecules having a wide range of mass from low molecular weight to high molecular weight are not capable of being measured by one medical diagnostic equipment. Since it is difficult to measure low molecular weight molecules such as drugs, metabolome, and the like, due to a matrix interference causing MALDI, the laser based MALDI-TOF has been mainly used for measuring high molecular weight molecules such as genes, proteins, and the like, and the ion beam based TOF-SIMS having a low sensitivity of the high molecular weight molecule has been used for measuring the low molecular weight molecules such as drugs, metabolome, and the like. Therefore, measuring equipment needs to be changed depending on molecular weight, which is inconvenient for measuring work, and equipment purchasing cost becomes increased.